TGFbeta3 SIGNALING IN DEVELOPMENT OF PALATE

味觉发育中的 TGFbeta3 信号传导

• 批准号: 7372341
• 负责人: Ali Nawshad
• 金额: $ 35.65万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7372341
• 关键词: Adhesions; Affect; Aging; Animals; Apoptosis; Apoptotic; Behavior; Biochemical; Biochemical Genetics; Biological Models; Cell Adhesion Molecules; Cell Cycle Arrest; Cell physiology; Cell-Cell Adhesion; Cells; Cellular biology; Chronology; Cleaved cell; Cleft Palate; Complex; Condition; Cultured Cells; Data; Deformity; Development; E-Cadherin; Elements; Embryo; Embryonic Development; Epithelial; Event; Extracellular Matrix; Face; Failure; Family member; Fibrosis; Genes; Genetic Transcription; Goals; Grant; Heart; Individual; Kidney; Knockout Mice; Knowledge; Lead; Lung; Malignant Neoplasms; Medial; Mediating; Mesenchymal; Mesenchyme; Molecular; Mus; Outcome Study; Palate; Pathway interactions; Phase; Phenotype; Prevention; Publishing; Research; Signal Pathway; Signal Transduction; Snails; Staging; System; Tissues; Transcription Coactivator; Transforming Growth Factors; activating transcription factor; base; cell motility; cell type; craniofacial; day; design; developmental disease; in vivo; insight; knowledge base; migration; novel; novel strategies; palatal shelves; palatogenesis; protein E; response; slug; transcription factor

DESCRIPTION (provided by applicant): Cleft palate, the most common craniofacial deformity in the USA, may caused by a failure of palatal medial edge seam (MES) cells to undergo complete disintegration, which is necessary in establishing confluence of the palatal stroma. While, Transforming Growth Factor (TGF) (-1, 2 and 3 are involved in palatogenesis, interestingly, TGF(3 is the only member of this family that is involved in palatal seam disintegration. TGF(3 signaling initiates and completes sequential phases of cellular differentiation that is required during MES disintegration, which progress between 14 to 17 embryonic days in the murine system. Understanding the cellular mechanism of palatal MES disintegration in response to TGF(3 signaling will result in new approaches to defining the causes of cleft palate and other facial clefts that may result from failure of seam disintegration. We have isolated MES primary cells to study the details of TGF(3 signaling mechanisms during palate development. To elucidate the mechanisms of MES disintegration by TGF(3, using several biochemical and genetic approaches, we demonstrated a novel mechanism of MES disintegration where MES undergoes cell cycle arrest, cell migration and apoptosis chronologically to generate immaculate palatal confluency during palatogenesis. We have shown that robust TGF(3 signaling induces both Smad dependent and Smad independent pathways to activate many transcription factors such as Snail, Slug, SIP1 and LEF1. It is unclear how these pathways and activated transcription factors promote cell cycle arrest, cell migration and apoptosis in the same cell type. We, therefore, wish to further study the mechanisms and diversity of TGF(3 signaling in MES cell function and how they are related to differential transcription factors and pathways to cause controlled MES disintegration. In this proposal, we would like to examine TGF(3 signaling towards these three individual cell functions. The broad objective of this grant is to understand the tissue transitions involved in the development of the palate and craniofacial mesenchyme in response to TGF( signaling. Each specific aim in the proposed study is designed to analyze the three phenotypical changes triggered by TGF(3, such as cell cycle arrest (Aim #1), migration (Aim #2) and apoptosis (Aim #3) required for MES disintegration to generate structural and functional component of the confluent palate. The rationale for this study is that successful completion of the proposed research will contribute to a missing, fundamental element to our base knowledge about the diverse functions of TGF(3 without which the cell cycle arrest, migration and apoptosis during MES disintegration cannot be understood. We believe that in some cases, knowledge of the basic cell biology will lead to more effective treatment of facial clefting.

描述（由申请人提供）：cleft裂，是美国最常见的颅面畸形，可能是由palatal骨内侧边缘接缝（MES）细胞失败而导致的，以实现完全崩解，这对于确定质基质的融合是必不可少的。同时，转化生长因子（TGF）（-1、2和3参与古质发生，有趣的是，TGF（3是该家族的唯一成员参与palatal接缝崩解的成员。TGF（3个信号引发并完成了MES分解过程中需要的细胞分解所需的细胞分化的顺序阶段，这是在MES分解过程中所必需的，这是在14到17个胚胎的模糊系统之间进行的。对TGF的响应崩解（3信号传导将导致新方法定义裂纹的原因和其他因接缝崩解失败而可能导致的面部裂缝。我们已经隔离了MES主细胞来研究TGF的细胞，以研究TGF的细节（3个信号传导机制在Palete and pales of Palate开发过程中的机制。 MES崩解的新型机制，其中ME经历了细胞周期停滞，细胞迁移和按时间顺序上的凋亡，以在古质发生过程中产生完美的palatal融合。我们已经表明，鲁棒的TGF（3个信号传导引起SMAD依赖和SMAD独立途径激活许多转录因子，例如蜗牛，SLUG，SIP1和LEF1。目前尚不清楚这些途径和激活的转录因子如何促进细胞周期的停滞，细胞迁移，细胞迁移，并在同一细胞类型中迁移。差异转录因子和导致MES崩解的途径。 TGF（3，例如细胞周期停滞（AIM＃1），迁移（AIM＃2）和凋亡（AIM＃3），以产生汇合口味的结构和功能成分所需的MES崩解所需。这项研究的理由是，拟议的研究的成功完成将有助于我们对TGF的多样化功能的基本知识的缺失，基本要素（3没有此，在MES崩解过程中细胞周期停止，迁移和凋亡是无法理解的。在某些情况下，我们认为，在某些情况下，对基本细胞生物学的了解将有效地治疗面对面孔的治疗。